The origin of the catalytic proficiency of the cofactor-independent enzyme proline racemase (ProR) has been investigated by a combined classical and quantum simulation approach with a hybrid quantum mechanics/molecular mechanics potential energy surface. The present study shows that the ProR reaction mechanism is asynchronous concerted with no distinct intermediate. Various mechanisms are investigated, and it is concluded that active site residues other than the Cys dyad are not involved in chemical catalysis. When compared to an analogous aqueous solution-phase reaction, we find that the free-energy barrier is reduced by 14 kcal/mol in ProR, although the reaction mechanisms in the enzyme and in water are similar. The computed catalytic effect is comparable to that in the isofunctional enzyme alanine racemase (AlaR). However, in AlaR the catalytic burden is divided between the cofactor pyridoxal 5'-phosphate and the enzyme environment, whereas in ProR it is borne entirely by the enzyme environment. This is ascribed to a highly preorganized active site facilitating transition state stabilization via a tight network of hydrogen bonds donated by nearby active site residues.